The sensitization response is an increased striatal dopaminergic response to a psychostimulant challenge that occurs in animals after repeated and prolonged exposure to a drug of abuse such as cocaine or amphetamine (Kalivas and Stewart, 1991;Robinson and Berridge, 1993;Vezina, 2004). This exaggerated DA response measured with microdialysis techniques is a well-validated and established phenomenon in the preclinical addiction literature. In sharp contrast to the chronic cocaine animals, three studies in cocaine dependent human subjects (CDS) have now reported a severe blunting (decrease) in the stimulant induced reduction in [11C]raclopride and [123I]IBZM in the striatum (and ventral striatum that includes the accumbens) (Malison et al., 1999;Martinez et al., 2006;Volkow et al., 1997). If one were to assume the decrease in [11C]raclopride binding following a stimulant challenge is purely reflective of presynaptic DA release, the results of the clinical imaging studies in humans suggesting a decreased dopaminergic tone (blunting) would be inconsistent with the preclinical studies in animals showing an increased dopaminergic tone (sensitization) following chronic and repeated exposure to cocaine. Nevertheless the smaller displacement of the antagonists [123I]IBZM or [11C]raclopride following stimulant challenge in CDS might result from a smaller increase in synaptic dopamine concentration following stimulants (i.e. presynaptic factors) or from decreased D2 receptor affinity for DA (i.e. postsynaptic factors), or from some combination of both factors. Available imaging methods do not allow to tease apart the respective contributions of these factors, because of the lack of radioligands to measure D2 agonist binding interactions. Despite the fact that D2 antagonist radioligands such as [123I]IBZM and [11C]raclopride have contributed tremendously to our understanding of dopamine transmission, they have been plagued by their relatively low sensitivity and ceiling effect (following stimulant challenges) which are presumably related to the fact that D2 antagonist bind to both high (D2high) and low (D2low) affinity states (Laruelle, 2000). The endogenous agonist dopamine is expected to compete efficiently with a D2 agonist radioligand such as [11C]NPA that binds preferentially to the agonist high affinity state than with an antagonist ligands such as [11C]raclopride that fails to distinguish between affinity states. Furthermore [11C]NPA is expected to have a smaller in vivo Bmax than [11C]raclopride for it binds to only a sub population of the binding of the antagonist radioligand (D2high and D2low). In this application we present evidence supporting both these hypotheses (Narendran et al., 2005;Narendran et al., 2004). This application proposes to further develop and characterize this radiotracer in healthy human subjects (test/retest reliability) and perform an exploratory study probing the role for decreased D2 agonist binding sites in cocaine dependence. PUBLIC HEALTH RELEVANCE: The overall goal of this application is to develop and validate a method that will make it possible to characterize the pre- or post-synaptic nature of the dysregulation of dopamine transmission revealed by the amphetamine challenge in patients with cocaine dependence.